title: Airway hyperresponsiveness to methacholine in mutant mice deficient in endothelin-1.
abstract: Endothelin-1 (ET-1) has recently been reported to have a potential pathophysiologic role in bronchial asthma. In the current study, we hypothesized whether ET-1 and a gene encoding ET-1 might be involved in airway hyperresponsiveness (AHR), which is a major feature of bronchial asthma. To test this hypothesis, we investigated airway responsiveness in ET-1(+/-) heterozygous knockout mice, which genetically produce lower levels of ET-1, and in ET-1(+/+) wild-type mice. Airway responsiveness was assessed through the concentration of an agonist required to double lung resistance (EC200 RL). Unexpectedly, airway responsiveness to methacholine was markedly enhanced in ET-1(+/-) heterozygous mice as compared with ET-1(+/+) wild-type mice (EC200 RL: 1.8 +/- 0.1 versus 21.6 +/- 5.6 mg/ml, p < 0.002). Pretreatment with the nitric oxide (NO) synthase inhibitor Ng-monomethyl-L-arginine (L-NMMA) significantly enhanced methacholine responsiveness in ET-1(+/+) wild-type mice, but not in ET-1(+/-) heterozygous mice. Meanwhile, there was no difference between ET-1(+/-) heterozygous mice and the wild-type mice in airway responsiveness to 5-hydroxytryptamine (5-HT). In sensitized mice, no significant differences in responsiveness to antigen were observed between the two groups. These findings suggest that the gene encoding ET-1 may be potentially involved in the etiology of airway hyperreactivity, and that the decrease in ET-1 concentration is associated with AHR to methacholine. In mice, ET-1 as well as NO may have a significant role in the homeostasis of airway physiology.
authors.affiliation: Department of Geriatrics, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Nagase
authors.forename: H
authors.initials: H
authors.lastname: Kurihara
authors.forename: Y
authors.initials: Y
authors.lastname: Kurihara
authors.forename: T
authors.initials: T
authors.lastname: Aoki
authors.forename: Y
authors.initials: Y
authors.lastname: Fukuchi
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Ouchi
mesh_terms: D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D019332:Endothelin-1 / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008168:Lung / Q000187:drug effects; D016210:Methacholine Chloride; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010047:Ovalbumin / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000276:immunology; D012701:Serotonin / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D016210:Methacholine Chloride; D019323:omega-N-Methylarginine; D012701:Serotonin; D010047:Ovalbumin; D019001:Nitric Oxide Synthase